Nature Reviews Molecular Cell Biology | AOP, published online 9 October 2008; doi:10.1038/nrm2528
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STEM CELLS — SCIENCE & SOCIETY
US policies on human embryonic
stem cells
Richard O. Hynes
Abstract | The United States is a federal union with separate state jurisdictions.
In part owing to the sometimes heated debate about public support for human
embryonic stem-cell (ESC) research, there has been restricted federal support
and little central regulation of this research to date. Instead, guidelines developed
by scientific organizations have set principles for oversight and good practice
for this research. These guidelines are functioning well, have influenced
developing state regulations and, one hopes, will affect any future federal
regulation.
In the decade since human embryonic stem-cell
(ESC, see Glossary) lines were first established1,2, research on this topic has proceeded
actively in the United States, despite major
restrictions on federal funding and an almost
complete absence of federal regulation.
Human ESCs are derived from cells of early
human embryos (FIG.1) and have the capacity
to develop into most different cell types and
tissues (see Glossary for further definitions
of relevant terms). This potential raises hopes
for their future use in regenerative medicine.
However, their derivation from embryos
raises issues for some people concerning the
ethical basis of human ESC research. Owing
to both its promise and the ethical debates,
human ESC research has been subject to
controversy, both in the United States and
elsewhere, and ethical, policy and political
discussions continue to this day.
These constraints have meant that the
principal source of funding for biomedical
research in the United States, the National
Institutes of Health (NIH), which would
otherwise have had a key role in funding and
regulating human ESC research, has had a
much smaller part in these processes. Instead,
scientific organizations have developed
guidelines to oversee this research and some
individual states have introduced their own
legislation and funding for human ESC
research, which has led to a patchwork of
rules and procedures.
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
Recent publications reporting the
reprogramming of somatic cells to pluripotent
cells by the introduction of exogenous
genes3–5 have introduced both new promise
in research and additional debate about
how research should proceed. As the Bush
administration enters its final months
of government, this seems an opportune
time to review the status of the science, its
funding and its regulation. There is strong,
though not universal, support for human
ESC research in the American public and
it seems likely that the next administration
and Congress will be more supportive of
the promise of human ESC research. Any
move to expand federal funding and oversight will necessitate the revision of policies
and regulations, taking into account the
background of existing procedures.
US federal policies
Although there are virtually no federal
laws that specifically regulate human ESC
research, local Institutional Review Boards
(IRBs) operating under the Common Rule,
a federal policy regarding the protection of
human subjects, govern federally supported
research that involves human subjects (BOX 1).
Many IRBs voluntarily apply the Common
Rule to all human subjects research, even if it
is privately funded. IRBs review and approve
human subjects research protocols, including
issues of informed consent and reimbursement. Therefore, donations of oocytes (eggs)
and embryos for human ESC research are
reviewed by IRBs. Similarly, introduction of
any cells into human patients requires IRB
review and approval. Furthermore, the Food
and Drug Administration (FDA) regulates
human clinical trials and the introduction
of all cells, tissues and devices into patients,
and has indicated its intention to include
human ESCs and their progeny under these
regulations (BOX 1).
However, none of these regulations
adequately addresses specific issues
pertaining to human ESCs, such as
their immortality and pluripotency, their
potential use in animal transplantation
experiments, in therapy and in commercial development. Given the sensitivity of
the ethical debates surrounding the use of
human embryos and other reproductive
materials (for example, eggs and sperm),
there is a clear need to monitor the derivation and use of human ESCs. However,
the federal government has not enacted
regulations that specifically cover human
ESC research. A brief historical review
Differentiation
ICM
Blastocyst
Established ESC lines
Figure 1 | Derivation of human embryonic stem cells. Embryonic stem cells (ESCs) are derived
from the inner cell mass (ICM) of an early embryo (blastocyst).Nature
ESCs Reviews
proliferate
continuously
when
| Molecular
Cell Biology
cultured under appropriate conditions. The potential to differentiate ESCs into most different cell
types in vitro raises great hopes for their future use in regenerative medicine.
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shows why this is so. This past history will
also affect future initiatives.
A historical perspective. In 1994, an NIH
advisory panel, acting under the NIH
Revitalization Act (1993), recommended
funding for the derivation of human ESCs
from surplus embryos in in vitro fertilization (IVF) clinics. This recommendation
came even before the isolation of human
ESCs. Once human ESC isolation had
occurred, President Clinton established a
National Bioethics Advisory Commission
(NBAC), which recommended in 1999 that
federal funds be made available for the derivation and use of human ESCs, and outlined
a national system of review and oversight of
human ESC research6. However, the use
of NIH or other federal funding to create
or destroy human embryos is prevented by
the so-called Dickey–Wicker amendment,
a congressional amendment that was first
introduced in 1996 and has been renewed
annually as a rider to the appropriations
(budgetary) bill for the Department of
Health and Human Services. This amendment effectively precludes the use of any
federal funds to generate human ESCs from
embryos. The NIH therefore developed
draft regulations that would allow the funding of research with existing human ESC
lines, but not their derivation. Those draft
…there is now general
agreement that only 20 or so
‘presidential’ lines are eligible
for NIH funding.
regulations were issued in August 2000, the
final year of the Clinton administration, but
the NIH could not fund any research before
the new administration halted the process
in early 2001.
After review and consultation, President
Bush announced on 9 August 2001 that the
NIH would be allowed to fund research
only on human ESC lines that had been
established before that date. He announced
that there were “more than 60” of such cell
lines, and directed the NIH to establish an
ESC register. Funding would be restricted
to experiments that used these approved
cell lines. This initially seemed to provide a
boost to human ESC research, but it soon
became clear that many of the cell lines were
either unavailable or unsuitable, and there
is now general agreement that only 20 or
so ‘presidential’ lines are eligible for NIH
funding (BOX 1). Furthermore, these lines
are inadequate in many ways (for example,
they were derived with outdated procedures, are contaminated by co-culture with
mouse cells and bovine serum products
Box 1 | Guidelines and regulations relevant to human embryonic stem cell research
National Research Council and Institute of Medicine of the National Academies, USA
Original guidelines (2005)9 and subsequent amendments10,11 are available for download at
http://dels.nas.edu/bls/stemcells/reports.shtml
The National Academies of Science also maintains links to sources of information about stem cells
at http://dels.nas.edu/bls/stemcells/introduction.shtml
International Society for Stem Cell Research (ISSCR) guidelines
Conduct of human embryonic stem cell research guidelines are available for download at
http://www.isscr.org/guidelines/index.htm
The ISSCR also maintains links to sources of information about stem cells at http://www.isscr.org/
public/index.htm
Stem cell information from the National Institutes of Health (NIH)
Information about the eligibility of stem cells for federal funding and the registry of approved lines
can be found at http://stemcells.nih.gov/
National Institutes of Health, Office of Human Subjects Research
http://ohsr.od.nih.gov/guidelines/45cfr46.html
US Department of Health and Human Services
The Basic Health and Human Services (HHS) Policy for Protection of Human Research Subjects is
available at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.110
US Food and Drug Administration (FDA)
The FDA oversees the introduction of all cells, tissues and devices into human patients.
Information about the work of the FDA can be found at the web sites below.
• http://www.fda.gov/cber/gene.htm
• http://www.fda.gov/cber/tiss.htm
• http://www.fda.gov/cber/devices.htm
• http://www.fda.gov/cber/genetherapy/clone.htm
2 | ADVANCE ONLINE PUBLICATION
and have probably deteriorated during
maintenance), and these inadequacies will
compromise their use in therapy.
Later lines made with improved procedures are thought to be superior, but are
ineligible for federal funding under the Bush
policy. Several attempts have been made to
expand the number of human ESC lines that
are eligible for federal support: most recently
a bill that was passed in 2007 by both houses
of Congress expanded support to all ‘ethically derived’ human ESC lines. However,
the bill was vetoed by President Bush, and
Congress could not override the veto. A
revised version of the bill (the Stem Cell
Research Enhancement Act) is now working its way through Congress, but seems
unlikely to be enacted during the remainder
of the Bush administration.
Current federal policies. Because of the
history summarized above, the NIH can
currently fund and regulate only a fraction of
useful human ESC research7. This research
does not include the sensitive topics of the
derivation of any new lines from embryos
or the use of any of the many newer lines
that have been derived using non-federal
funds. As in any new field, the first round
of research materials are usually replaced
by improved versions as scientists learn to
tackle the new area effectively. However,
under the Bush policies, NIH-funded
researchers are restricted to working on
the older presidential human ESC lines,
which are generally agreed to be deficient.
Furthermore, NIH policy specifies that
research with non-approved lines cannot be
“directly or indirectly” supported by federal
funds (BOX 1). This means that research using
non-presidential lines cannot be conducted
using personnel, reagents, equipment or
even laboratory space that are even partially
supported by federal funds, without complex
cost allocations. This means that, even if
a scientist obtains non-federal support to
conduct human ESC research on state-ofthe-art, newly derived human ESC lines, that
research must be conducted with personnel,
equipment and supplies seperate from those
supported by federal funds. This inevitably
increases the costs of the research, because
additional (and often duplicated) laboratory
space and equipment are required, and significant opportunity costs are expended on
monitoring compliance.
These rules also block any researchers
without non-federal support from human
ESC research using the best lines. This is
a major impediment to the advance of the
field, as the NIH provides the principal
www.nature.com/reviews/molcellbio
PERSPECTIVES
funding of biomedical research in the
United States. Passage of the Stem Cell
Research Enhancement Act would remove
these significant restrictions to the benefit
of research, without crossing any new ethical boundaries. Unfortunately, the Bush
administration seems steadfastly resistant to
expanding support for human ESC research,
and progress will have to await a new
administration.
The polarization of the political debate
has also ensured that no federal legislation
to regulate human ESC research or IVF has
been passed by Congress. That includes a
failure to ban or restrict human reproductive
cloning, although most people on both sides
of the debate agree that this should not be
allowed. The FDA has stated that attempts
to perform reproductive cloning would be
a form of cell-based therapy that is subject
to FDA regulations, and that it would not
currently approve any such procedure.
Therefore, reproductive cloning could be
subject to criminal and financial penalties
for violating FDA regulations. Professional
groups, including the American Society
for Reproductive Medicine (ASRM), the
National Academies of Science (NAS) and
the International Society for Stem Cell
Research (ISSCR), have gone on record to
oppose any attempts to reproductively clone
humans.
Guidelines for human ESC research
The vacuum in federal leadership in the face
of a promising and rapidly advancing field of
research that, at the same time, raises ethical
and policy issues, meant that human ESC
research proceeded with essentially no guidelines for appropriate conduct and procedures.
Individual states were introducing either
diverse regulatory systems or none at all,
and research funded by private sources was
underway with almost no oversight. This was
felt to be highly undesirable, both from a policy perspective and also in terms of the future
directions of the science. Scientific progress
relies on the sharing of cell lines, which were
being derived with differing and sometimes
inadequate attention to ethical procedures.
This concern has recently surfaced anew with
an ironic twist; it seems that several of the
NIH-approved presidential lines were derived
with informed consent procedures that fall
short of current ethical standards8.
Because of these concerns about the
absence of federal government regulations,
responsible scientists desired guidelines
for the appropriate conduct of human
ESC research. Accordingly, in 2004, the
National Research Council and the Institute
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
Box 2 | Policies in individual states
Iowa
New York
Wisconsin
Massachusetts
Connecticut
New Jersey
Maryland
Illinois
Missouri
California
States currently endorsing and providing support for human ESC research
The links below direct to web sites of state-specific regulationsCVijgZGZk^ZlhqBdaZXjaVg8Zaa7^dad\n
(see figure).
California. Two sets of standards, one covering research supported by the California Institute for
Regenerative Medicine (CIRM) and the other covering research funded from other sources.
CIRM regulations can be found at http://www.cirm.ca.gov/reg/default.asp
Connecticut. http://www.ct.gov/dph/cwp/view.asp?a=3142&q=389702&dphNav_GID=1825
Illinois. http://www.illinois.gov/gov/execorder.cfm?eorder=46
Iowa. http://coolice.legis.state.ia.us/Cool-ICE/default.asp?category=billinfo&service=billbook&GA
=82&hbill=SF162
Maryland. http://www.mscrf.org/content/aboutus/actof2006.cfm
Massachusetts. http://www.mass.gov/legis/laws/seslaw05/sl050027.htm
Missouri. http://www.sos.mo.gov/elections/2006petitions/ppStemCell.asp
New Jersey. http://www.state.nj.us/scitech/stemcell/
New York. http://stemcell.ny.gov/
Wisconsin. http://www.wisgov.state.wi.us/journal_media_detail.asp?locid=19&prid=1943 and
http://www.stemcells.wisc.edu/
For more information on individual state regulations, see:
Interstate Alliance on Stem Cell Research. This site has a listing of state stem-cell programmes with
links to individual state regulations. It also has available for download a useful summary table of
state policies compiled by S. Stayn, who has also published on the issue of the need for conformity
among guidelines and individual state regulations 16,17. The web site can be found at http://www.
iascr.org/states.shtml
National Conference of State Legislatures. This site has a listing of state stem-cell programmes with
links to individual state regulations, and also lists states that have enacted prohibitions on certain
types of research. The web site can be found at http://www.ncsl.org/programs/health/genetics/
embfet.htm
See online for an interactive version of this box.
of Medicine of the NAS convened a committee to develop guidelines for human
ESC research, and in 2006, the ISSCR did
the same. These two committees published
their sets of guidelines in April 2005
(REFS 9–12) and December 2006 (REFS 13,14),
respectively, and these have since served as
the basis for the oversight of human ESC
research. Although the NAS guidelines
were developed specifically for the United
States, they incorporated many features
from existing legislation in other countries,
particularly the United Kingdom and
Canada. Similarly, the ISSCR guidelines,
although intended to be applicable in many
countries, adopted many features of the NAS
guidelines, as did many US states in writing
their own regulations. There has been a continuing effort to seek concordance among
different sets of guidelines and, although
they necessarily differ in some details
because of their differing contexts, there is
good agreement on the major principles that
underlie their rules.
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Glossary
Chimaera
An organism that is composed of cells from at least two
genetically different sources. The cells could be from the
same or separate species.
Cybrid
A cell with a nucleus from one cell and cytoplasm from
another. For example, it is possible to reprogramme a
somatic cell nucleus by inserting it into the cytoplasm of
an oocyte or another pluripotent cell.
Embryonic stem cell
(ESC). A primitive (undifferentiated) cell that is derived
from early embryos. These are usually derived from the
blastocyst (50–250-cell stage), but are sometimes
derived from the morula (16–32-cell stage). ESCs have
the potential to become a wide range of specialized
cell types.
germ layers (endoderm, ectoderm and mesoderm) and
most cells and tissues of an embryo.
Reproductive cloning
The generation of viable organisms from cloned
pluripotent cells.
Reprogramming
The alteration of the epigenetic programme of a
nucleus or cell to change its differentiation capacity.
For example, a differentiated cell of limited potential is
reprogrammed by nuclear transfer (NT) or by the
introduction of exogenous genes (currently using
retroviruses but alternative methods are being
researched).
Retroviruses
A cell that has been derived from a somatic cell by
reprogramming the nucleus to induce pluripotency,
using exogenous genes or other factors.
RNA viruses that are used as carriers or vectors to
introduce genes into the genomes of cells.
Retroviruses are used in basic research and have
been used in gene therapy, in which they have been
reported to induce cancer in a limited number of
patients.
Nuclear transfer
Somatic cell
(NT). Replacing the nucleus of a cell with the nucleus of
another cell.
Any cell other than a germ cell or a germ-cell precursor.
Induced pluripotent stem (iPS) cell
Stem cell
Pluripotency
The capacity of a cell to develop into cells of all three
Both the NAS and ISSCR guidelines
prohibit human reproductive cloning and the
in vitro culture of human embryos beyond
14 days or beyond the development of the
embryonic axis. Both lay out clear rules
regarding the acquisition of eggs, embryos
and other cell types for generating human
ESC lines, including the necessity for appropriately detailed and informed consent, and
both require review and approval by an IRB
or equivalent panel. Both sets of guidelines
allow the derivation of human ESC lines
from excess embryos from IVF clinics, from
embryos created explicitly for human ESC
research, from oocytes into which the
nuclei of other cells have been introduced
by nuclear transfer (NT) or from single cells
obtained from embryos (for example, during pre-implantation genetic diagnosis). It
is of interest that both the NAS and ISSCR
guidelines include, among their informed
consent items, the possibility of interspecies
mixing. The background section of the NAS
guidelines explicitly mentions the possible
use of cybrids, in which human somatic cell
nuclei are introduced into enucleated animal
oocytes to induce reprogramming. Such procedures were recently approved in the United
Kingdom, but only after considerable debate
about intermixing of species (see the article
by Lovell-Badge in this issue).
Both the NAS and ISSCR guidelines allow
reimbursements of ‘reasonable costs’ that have
4 | ADVANCE ONLINE PUBLICATION
A cell that has the ability to divide extensively in vivo or
in culture and to give rise to specialized cells.
been incurred during the donation of oocytes,
embryos or other materials, but preclude the
payment of ‘valuable consideration’ (payments beyond reimbursement for expenses)
for such donations. The precise definitions of
reasonable costs and valuable consideration
differ slightly and are undergoing continual
review by both the NAS and the ISSCR, and
by states that have adopted similar rules (see
below). Nonetheless, both sets of guidelines
adhere to the principle that ‘undue inducements’ to donate and the commodification
of reproductive materials should both be
avoided. The appropriate recompense for
donations, especially of oocytes, is a complex
issue with sound arguments on all sides and
a full discussion is beyond the space available
here. Interested readers should refer to the
specific guidelines in which the issues are
discussed extensively (BOX 1).
Both the NAS and ISSCR guidelines
make detailed recommendations about the
distribution, sharing and banking of human
ESC lines, which will be essential as the
research proceeds. The guidelines do not
…the NAS and ISSCR
guidelines […] lay out clear rules
regarding the acquisition of eggs,
embryos and other cell types for
generating human ESC lines…
address clinical trials — as mentioned, clinical trials in the United States fall under FDA
regulations and local IRB oversight.
Oversight committees. The NAS and ISSCR
guidelines require the review of all human
ESC research by a qualified panel that
includes scientists, ethicists and representatives of the public (this panel is commonly
called an Embryonic Stem Cell Research
Oversight (ESCRO or SCRO) committee).
These committees must document the provenance of any human ESC lines to be used,
review and approve the research proposed
and keep a record of human ESC research
underway at each institution. The ESCRO
committee is also responsible for coordinating other necessary reviews, for example, by
IRBs for studies in which the derivation of
human ESC lines or other human subjects
research are involved, or by animal research
oversight committees if the introduction
of human ESCs or their descendants into
animals is proposed.
The issues associated with the introduction of human ESCs and other stem cells into
animals (chimaera research) have raised their
own set of controversies about the mixing of
species. Many concerns about research using
chimaeras are a consequence of the failure
to understand the necessity for such experiments in preclinical testing of human ESCs
and their descendants, en route to therapeutic
applications. In addition, most chimaera
experiments (which are routine in biological
research) have no particular ethical concerns
beyond those that concern animal welfare,
and such concerns are already well regulated
by animal research oversight committees.
There are a few potential concerns regarding
the introduction of neural progenitors (either
human ESC-derived or from other sources)
into animals, as these might incorporate into
and affect the brain, or the introduction of
cells that might contribute to the germ line
and gametes (sperm and eggs). The NAS and
ISSCR guidelines provide advice to ESCRO
committees as to which experiments need
special monitoring. As research proceeds with
appropriate oversight, it will become clear
which, if indeed any, of these experiments
actually present any concerns.
As the guidelines were developed, it was
noted that stem cells of other types (for
example, neural stem cells) present some of
the same issues as human ESCs when introduced into animals. With the development
of induced pluripotent stem (iPS) cells by the
reprogramming of somatic nuclei to induce
pluripotency3,4,5 (the ability to differentiate
into multiple cell types, including neural
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cells and gametes), it has become clear
that other cells also need to be reviewed by
ESCRO committees for some experiments,
especially those that involve introduction into
animals. Both the NAS and ISSCR are currently reviewing their guidelines in recognition of the issues raised by these new cells. It is
worth noting that iPS cells might have much
of the same potential as human ESCs for the
generation of many differentiated cells for
use in regenerative medicine, and some have
suggested that they obviate the need for continued human ESC research. This is far from
the truth. iPS cells need much further validation, including extensive comparisons with
human ESCs to determine their full potential.
Furthermore, current protocols for deriving
iPS cells use retroviruses, and the introduction
of such viruses has been known to cause
cancer in gene therapy trials15. Clearly, further
research will be required to develop either iPS
or human ESCs to realize their full potential
for therapeutic applications and it is incorrect
to suggest that further research on either one
is unnecessary.
The ESCRO committee system is working
well — most institutions that conduct human
ESC research in the United States have either
established such committees or have access
to ESCRO committees that are shared with
other institutions. The distributed style of
oversight conforms with the mechanisms
that are used in the United States for the local
review of human and animal research. The
ability of scientists working with their own
professional organizations to oversee human
ESC research in the absence of central government regulation has been well received,
and forms the template on which certain
individual states have established their own
regulatory and funding policies.
Stem-cell research in individual states
Although most states do not have regulations that govern human ESC research,
some do prohibit certain experiments with
human embryos or fetuses, which effectively precludes human ESC derivation.
Around a dozen states explicitly endorse
human ESC research, including derivation,
although there are differences in the details
of what is approved where. Several states
also provide funding for human ESC and
other stem-cell research (BOX 2 collects
current information along with references
and web sites for up-to-date information).
Where detailed regulations have been
promulgated, they closely follow the principles of the NAS guidelines, although there
are, of course, differences in detail, and the
scene is constantly changing16,17.
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
Within the various states, the ESCRO
committee system operates uniformly,
although there are variations in response
to individual state laws. The diversity of
state regulations has the obvious potential
to interfere with interstate collaborations,
particularly if the regulations are notably
divergent in different jurisdictions. This
issue also applies to international collaborations. The NAS and ISSCR guidelines were
written taking this potential for discordancy
among regulations into consideration and, in
general, the same has been true of individual
states. There are ongoing efforts to coordinate guidelines and regulations among states,
such as the Interstate Alliance on Stem Cell
Research (IASCR), and both the IASCR and
the National Conference of State Legislatures
have web sites with useful information about
the regulations in different states.
Conclusions and perspectives
Human ESC research is proceeding actively
in the United States, despite rather limited
federal support under the current administration. In the absence of specific federal regulations, scientific organizations have developed
guidelines for the responsible conduct of
the research and these are operating well.
Individual states that have endorsed, and in
some cases, funded, human ESC research,
have adapted the guidelines and developed
their own regulations. As science develops,
one hopes with greater federal support in the
future, it will be important for the rules and
regulations in different jurisdictions to be
written so as to enhance, rather than inhibit,
collaboration and exchange among scientists
in different states and countries. The template
of the existing guidelines and the ESCRO
committee mechanism is already serving as
a good base for developing state regulations.
It seems probable that the next Congress and
presidential administration will modify or
remove the restrictions on federal funding of
human ESC lines that were developed before
August 2001. This in itself would provide
a considerable boost to human stem-cell
research in the United States.
The prospects for federal funding of the
derivation of new human ESC lines from
embryos seem much slimmer. However,
the rapidly advancing development of iPS
cells, which lack the ethical complications of
derivation from embryos18, seems certain to
provide pluripotent stem cells for research
purposes. Development of either human
ESCs or iPS cells for therapy requires additional research to overcome existing technical hurdles and one hopes that the public
policy, ethical and federal funding issues that
have slowed this research during the past
decade will become less of an impediment in
the future.
Richard Hynes is at the Howard Hughes Medical
Institute, David H. Koch Institute for Integrative Cancer
Research, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139-4307, USA.
e-mail: [email protected]
doi:10.1038/nrm2528
Published online 9 October 2008
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Acknowledgements
The author would like to thank A. Charo, G. Daley, F. Sharples,
S. Stayn and K. Wilson for their helpful suggestions on the
content of this article.
FURTHER INFORMATION
Richard Hyne’s homepage: http://web.mit.edu/ccrhq/
hyneslab
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